Drug delivery devices useful for introducing therapeutic molecules into a mammal have been the subject of considerable research. In one aspect, the research has focused on the development of devices that deliver molecules produced from cellular metabolism. Efforts have also focused on producing an implantable cell based delivery system that can remain in a patient for an extended period of time.
An implantable device for delivering a pre-selected molecule, for example, a hormone, into a mammal's systemic circulation is described in U.S. Pat. No. 6,716,208, the entire contents of which is incorporated by reference. The device described comprises an implantable blood permeable element that can be anchored to an inner wall of an intact blood vessel and a capsule that is held in place within the blood vessel by the anchored blood permeable element. The capsule encloses viable cells which produce and secrete the preselected molecule into blood passing the capsule. The patent also describes a method for percutaneously introducing the device into a preselected blood vessel.
Intracorporeal cell based delivery devices must be sized to fit within a body, typically a body lumen (such as a blood vessel) and, accordingly, have certain size limitations because of the reduced-size requirements. Further, when an intracorporeal cell based delivery system is designed, the anchors used to attach the device to the body, e.g., blood vessel, must be configured to secure the device without introducing trauma to the body. Finally, implantable devices can be difficult to retrieve, especially if they are left within the body for an extended period of time.
In vitro experiments with a larger extracorporeal device utilizing porcine or human proximal tubule progenitor cells have shown differentiated transport and metabolic functions of the renal tubule assist device (RAD).[references 4-6] The bioartificial kidney (BAK) set-up consists of a filtration unit (a conventional synthetic hemofiltration cartridge) followed in series by the tubule (RAD) unit. The tubule unit is able to maintain viability because oxygen along with metabolic substrates and growth substances are delivered to the tubule cells from both intraluminal ultrafiltrate and blood in the extracapillary space. Immunoprotection of the cells is achieved due to the impenetrability of immunoglobulins and immunocompetent cells across the hollow fibers. Rejection of non-autologous cells does not occur.
Pre-clinical studies in large animals have demonstrated that the BAK successfully replaced filtration, transport, metabolic, and endocrinologic functions of the kidney in acutely uremic dogs.[5] Further pre-clinical experiments in acutely uremic dogs have also evaluated the influence of the RAD under stress states. Acutely nephrectomized animals were challenged with infusions of endotoxin (lipopolysaccharide) intravenously or with intraperitoneal administration of doses of viable E. Coli before treatment with either cell or sham control RADs in a BAK.[references 7,8] In these experiments, cell RADs provided metabolic renal replacement and resulted in higher anti-inflammatory plasma levels, better hemodynamic stability, and, in the E. Coli sepsis model, longer survival times compared to sham controls. To further evaluate the role of the BAK in septic shock, a swine model with normal kidney function was given large doses of E. Coli intraperitoneally.[reference 9] All animals developed acute tubular necrosis with oligo/anuria within 2-4 hours following administration, and RAD treatment resulted in better cardiovascular performance, lower plasma levels of the pro-inflammatory cytokines, and longer survival times compared to sham controls.
These supportive pre-clinical experiments were the basis for testing human cell RADs in Phase I/II and Phase II clinical trials in intensive care unit (ICU) patients with ARF and MOF. A favorable Phase I/II safety trial [reference 10] led to an FDA-approved, randomized, controlled, open-label Phase II investigation at 12 clinical sites to determine whether this cell therapy approach alters patient mortality. This Phase II study involved 58 patients, of whom 40 were randomized to RAD therapy and 18 made up a control group with comparable demographics and severity of illness. The early results have been as compelling as the Phase I/II results. Renal cell therapy improved the 28-day mortality rate from 61% in the conventional hemofiltration-treated control group to 34% in the RAD-treated group.[references 11,12] This survival impact continued through the 90- and 180-day follow-up periods (p<0.04), with the Cox proportional hazard ratio indicating that the risk of death was 50% of that observed in the conventional continuous renal replacement therapy group. This survival advantage with renal cell therapy was observed for various etiologies of ARF and regardless of organ failure number (1 to 5+) or the presence of sepsis. Subset analysis of patients with concomitant severe sepsis or septic shock demonstrated an incidence of sepsis of 73% and 67% in the cell therapy and conventional therapy groups, respectively. RAD therapy was associated with a mortality rate of 34% in patients with sepsis, compared to 67% in the conventional treatment group. Thus, these clinical results suggest a major effect on survival rates in these desperately ill patients. The clinical use of renal tubule cell therapy for patients with severe sepsis will not require this complex two-cartridge system with two extracorporeal pump systems, since most are not in ARF.
The present invention provides an extracorporeal cell based delivery system that is designed to address aspects of an intracorporeal cell based delivery system. Further, the present invention provides an extracorporeal device designed to introduce therapeutic agents into a mammal that secretes a pre-selected molecule or a combination of cell products directly into the blood stream or into a body fluid or body cavity and addresses the challenges of the prior art. The invention will be more clearly understood from the description, which follows.
Further, a miniaturized cell therapy device will not require extensive extracorporeal blood pump systems. In addition, a miniaturized device that could be stored at the clinical site for immediate use is required to succeed as a commercial product. The current RAD is stored at a central manufacturing facility at 37° C. and must be shipped at 37° C. to the clinical site, delaying treatment and adding to the cost of therapy. Development of a cell device that can be cryopreserved and stored at clinical sites can help safetly bring the device to market.